Jerome R. Ryan

Evaluation of Intramuscular Levonantradol and Placebo in Acute Postoperative Pain

Abstract: Double‐blind administration of a single intramuscular dose of 1.5, 2.0, 2.5, or 3.0 mg levonantradol or placebo to 56 patients with moderate to severe postoperative or trauma pain showed significant analgesic effects of each dose of levonantradol as compared to placebo (P < 0.05). However, no significant dose response was observed. Compared to 2/16 patients on placebo, 23/40 patients (57 per cent) on levonantradol reported one or more side effect. Drowsiness was most frequent. Dry mouth, dizziness, “weird dreams,” mild hallucinations, nervousness, apprehension and confusion occurred less frequently. Changes in resting heart rate and blood pressure were minor and general acceptability was good.

Upper gastrointestinal endoscopy in normal asymptomatic volunteers

In a prospective study, 355 healthy, asymptomatic, male volunteers, 18 to 45 years of age, were screened by esophagogastroduodenoscopy before admission to clinical trials. One hundred thirty-four volunteers (38%) showed abnormal endoscopic findings. Some volunteers had more than one site of involvement or more than one grade of lesion in each anatomic location. In 49 (14%) of these subjects the esophagus was a site of involvement, while in 86 (24%) the stomach was involved, and in 71 (20%) the duodenum was involved. The point prevalences in these asymptomatic subjects were 8.5% for erosive esophagitis, 12% for erosive gastritis, 10% for erosive duodenitis, 2% for gastric ulcer, and 2% for duodenal ulcer.

ANALGESIC EFFICACY OF LOW-DOSE IBUPROFEN IN DENTAL EXTRACTION PAIN

A single‐dose, double‐blind, randomized, parallel trial was conducted to compare the analgesic efficacy of oral ibuprofen (I) 100, 200, or 400 mg, aspirin (ASA) 650 mg, and placebo in moderate to severe pain after extraction of impacted teeth. Subjective, self‐evaluated pain intensity and pain relief reports, hourly for 6 hours, were used as indexes of analgesic response. Data on 227 evaluable patients showed significant differences among the 4 active treatments and placebo (p < 0.001) by most measurements of analgesia. Although no consistent, significant differences were observed among the active drugs, I 400 mg performed the best, followed by I 200 mg, ASA 650 mg, and I 100 mg. Remedication was required by 59% patients receiving I 400 mg, 67% taking I 200 mg, 73% taking ASA 650 mg, 74% taking I 100 mg, and 96% receiving placebo. Differences between I 400 mg and I 100 mg were significant for remedication data (p < 0.05). Side effects were minor, infrequent, and not dose related. In this study, I 100 mg was distinctly superior to placebo and probably as effective as ASA 650 mg in relieving pain. Only a shallow dose response of ibuprofen was observed.

Potentiation of Hypoglycemic Effect of Sulfonylureas by Halofenate

We investigated the possibility of a drug interaction between the antilipemic agent halofenate and sulfonylureas. Twelve young, healthy men were given 1 g of tolbutamide by mouth before and after 12 days of double-blind treatment with 1 g per day of halofenate, or placebo. There was a significant increase in serum tolbutamide at eight, 10 and 12 hours (P less than 0.01) and a significant (P less than 0.01) decrease in serum glucose at one, four and six hours after halofenate treatment, but not after placebo. In a long-term, double-blind study of halofenate or clofibrate treatment of patients with Type IV hyperlipoproteinemia, diabetic patients receiving a sulfonylurea and halofenate either required a reduction in the dose of the sulfonylurea or demonstrated significantly improved control of hyperglycemia (P less than 0.05) or both. No appreciable decrease in serum glucose levels was noted in diabetic patients receiving sulfonylurea and clofibrate. This interaction between halofenate and sulfonylureas is clinically important, especially in view of the association of hyperlipemia and diabetes.

The effect of MK‐185 on some aspects of uric acid metabolism

Following oral administration of MK‐185 to 10 patients with types III, IV, or V hyperlipoproteinemia at doses of 10, 15, and 20 mg. per kilogram per day for a period of 4 weeks at each of the 3 dose levels, the serum uric acid decreased significantly with the progression of dosage. A specific metabolic study designed to evaluate the mechanism of this hypouricemic action showed that MK‐185, 20 mg. per kilogram per day for 3 days, produced a gradually increasing (p < 0.05) uricosuria in the 3 patients studied. The results of the other drugs used in metabolic study, namely, probenecid, allopurinol, and clofibrate are discussed in relation to those of MK‐185.

Role of misoprostol in reducing aspirin-induced gastrointestinal blood loss in arthritic patients

Nonsteroidal anti-inflammatory drugs are used to control pain and inflammation in arthritic disorders. When used at recommended anti-inflammatory dose levels, however, they often produce injury to the gastric and duodenal mucosa and concomitant blood loss. A double-blind, parallel, placebo-controlled study was conducted to assess the effectiveness of misoprostol, a synthetic analogue of prostaglandin E1, in preventing gastrointestinal blood loss induced by acetylsalicylic acid in patients with degenerative joint disease. Forty-five arthritic patients (22 women and 23 men) were admitted to the study. All patients had received treatment with 3,900 mg of acetylsalicylic acid per day in four divided doses for at least two weeks and continued to receive that regimen for the duration of the study. Red blood cells were tagged with chromium-51, and fecal blood loss was determined from Days 4 to 7. Patients with a mean blood loss of at least 1.5 ml per day were randomly allocated to receive either placebo or 200 micrograms of misoprostol four times daily for seven days. Fecal blood loss was measured daily, and the results were compared with baseline determinations. Of 41 patients who completed the study, 19 were treated with misoprostol. Of these, 11 patients (57.9 percent) had at least a 50 percent reduction in blood loss. Of 22 patients receiving placebo, only one had a 50 percent reduction in blood loss (p = 0.003; Fishers exact test). Mean blood loss in patients using misoprostol was reduced from 3.65 +/- 2.51 to 1.57 +/- 0.86 ml per day, whereas among those taking placebo, mean blood loss did not significantly change (2.98 +/- 1.24 to 2.79 +/- 1.63 ml per day). The difference in blood loss between the misoprostol and placebo groups was significant (p = 0.0023; Wilcoxon test). In those patients who completed the study, no significant changes were detected on laboratory tests. In conclusion, misoprostol effectively reduced fecal blood loss in arthritic patients treated with acetylsalicylic acid.

Effect of potassium chloride supplements on upper gastrointestinal mucosa

Eight controlled 1‐ or 2‐wk experiments involving 225 healthy male subjects and one study of 18 patients with hypertension, nine of whom were long‐term users of a wax‐matrix potassium chloride preparation, were conducted to evaluate the upper gastrointestinal safety of oral KCl supplements. All subjects in the short‐term studies had normal upper gastrointestinal tracts. Subjects were examined again after at least 7 days of treatment with one of three commonly prescribed wax‐matrix KCl tablets, KCl liquid, microencapsulated KCl, a potassium‐sparer, or placebo. Some received an anticholinergic drug with treatment to induce delayed gastric motility. Diet and compliance to treatment regimens were controlled. Results indicate that upper mucosal injury, particularly erosions (43%) and ulcerations (11%), were more frequent after wax‐matrix tablets. These changes occurred much less frequently after liquid KCl (0%), microencapsulated KCl (10.5% erosions, 1.2% ulcers), and the potassium‐sparing drug (0%). More serious and more frequent lesions were associated with slowed motility. No occult bleeding was noted. Symptomatic complaints did not correlate with endoscopic findings. In the long‐term study, patients with hypertension were examined endoscopically after 19 to 23 mo on KCl and again after 1 wk. Six of nine of the patients with hypertension treated for nearly 2 yr with a wax‐matrix KCl supplement had significant lesions. One had developed ulceration after 7 days. The incidence of lesions was lower in a carefully matched group of controls who received only placebo (erosions in three of nine; none had or developed ulcers). Incidence of upper mucosal injury with wax‐matrix tablets is higher than with other liquid or microencapsulated forms of KCl or with a potassium‐sparing drug.

Efficacy and acceptability of different dosage schedules of clonidine

In 12 hospitalized patients with hypertension, clonidine 3 times a day led to better control of blood pressure than did the same total dose administered once daily. Compared to the uniform control of blood pressure on divided dose regimen, the single daily 8 p.m. dose led to wider fluctuations and inadequate control 18 hr after dosing. However, 10 of the 12 patients preferred the single daily dose at 8:00 p.m. to the divided dose regimen because of no drowsiness during the day. In 2 patients administration of clonidine twice daily resulted in better control of blood pressure than that du ring the single or thrice‐daily dose regimens. Since there appeared to be a correlation between the dose and the duration of adequate blood pressure control, administration of clonidine twice a day with a larger dose at bedtime and a sm aller dose before noon could limit unwanted drowsiness and combine the convenience of less frequent dosing with superior blood pressure control.

Comparison of oral nalbuphine acetaminophen and their combination in postoperative pain

This double‐blind, randomized, parallel, placebo‐controlled study evaluated the analgesic effects of single oral doses of 30 mg nalbuphine, 650 mg acetaminophen, and the contribution of each to the efficacy of their combination in 128 hospitalized patients with postoperative pain. Subjective reports of patients evaluated each hour for 6 hours were used as indices of analgesic response. Both nalbuphine and acetaminophen were significantly superior to placebo for most measures of total and peak analgesia. The interaction contrast between nalbuphine and acetaminophen was not significant for any analgesic measurements, indicating an additive effect of the components. The combination was the most effective treatment, followed by nalbuphine, acetaminophen, and placebo. Effects of the combination were significantly different from those of acetaminophen at 4, 5, and 6 hours and from those of placebo at 1 to 6 hours. There was no significant difference in the frequency or intensity of side effects among the groups. The combination of nalbuphine and acetaminophen appears to be a therapeutically useful combination.

The influence of liver dysfunction on the pharmacokinetics of carprofen

The pharmacokinetics of the investigational agent carprofen were examined in 12 patients with liver dysfunction (hepatic cirrhosis) and in six normal volunteers following single 100‐mg oral administration of carprofen. In addition, three patients with acute hepatitis received a single 100‐mg dose during the acute phase of the disease, and two of these patients received the same dose after they had convalesced. The pharmacokinetic parameters and urinary excretion data did not differ significantly (P > 0.05) between patients with hepatic cirrhosis and healthy volunteers. The mean ± SD area under plasma concentration‐time curve and apparent oral plasma clearance values were 57.8 ± 11.7 μg × h/mL and 30.0 ± 6.3 mL/min, respectively, in patients and 52.4 ± 11.3 μg × h/mL and 33.1 ± 7.2 mh/min in normals. The respective harmonic mean elimination half‐lives were 10.5 and 9.4 hours. The 0–24 hour urinary recovery of intact drug and the glucuronide conjugate were 7.0 ± 4.9% and 28.9 ± 11.0%, respectively, in patients compared to 5.5 ± 7.1% and 20.1 ± 12.3% in normal subjects. The results of this study showed that liver dysfunction (hepatic cirrhosis) had no effect on the pharmacokinetic profile of carprofen. In the two patients with acute hepatitis who completed the study, the results suggest that the apparent oral clearance of carprofen may increase during the acute phase of the disease.